Autism spectrum disorder causes, mechanisms, and treatments: focus on neuronal synapses

Won, Hyejung; Mah, Won; Kim, Eun Joon

doi:10.3389/fnmol.2013.00019

Cited by 170 publications

(151 citation statements)

References 328 publications

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“…ASD is characterized by deficits in social interaction and communication, restricted interests, and repetitive behaviors, and the aberrant development and function of synapses is known to be involved in its pathogenesis [62] .…”

Section: Neurodevelopmental Disordersmentioning

confidence: 99%

Autophagy in synaptic development, function, and pathology

et al. 2015

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In the nervous system, neurons contact each other to form neuronal circuits and drive behavior, relying heavily on synaptic connections. The proper development and growth of synapses allows functional transmission of electrical information between neurons or between neurons and muscle fi bers. Defects in synapse-formation or development lead to many diseases. Autophagy, a major determinant of protein turnover, is an essential process that takes place in developing synapses. During the induction of autophagy, proteins and cytoplasmic components are encapsulated in autophagosomes, which fuse with lysosomes to form autolysosomes. The cargoes are subsequently degraded and recycled. However, aberrant autophagic activity may lead to synaptic dysfunction, which is a common pathological characteristic in several disorders. Here, we review the current understanding of autophagy in regulating synaptic development and function. In addition, autophagy-related synaptic dysfunction in human diseases is also summarized.

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Section: Neurodevelopmental Disordersmentioning

confidence: 99%

Autophagy in synaptic development, function, and pathology

et al. 2015

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“…While previous studies have demonstrated that miR-137 regulates dendritic development both in vitro and in vivo in adult granule neurons 7,9 , the function of miR-137 in the presynaptic compartment remains unexplored. It is crucial to elucidate the functional consequences of psychiatric-associated gene variants as cognitive and synaptic dysfunctions are phenotypes common to schizophrenia and autism spectrum disorders 10,11 .…”

Section: Introductionmentioning

confidence: 99%

The Schizophrenia Risk Gene Product Mir-137 Alters Presynaptic Plasticity

Siegert

Seo

Kwon

et al. 2017

European Neuropsychopharmacology

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Non-coding variants in the human MIR137 gene locus increase schizophrenia risk at a genomewide significance level. However, the functional consequence of these risk alleles is unknown. Here, we examined induced human neurons harboring the minor alleles of four disease-associated single nucleotide polymorphisms (SNPs) in MIR137, and observed increased MIR137 levels compared to major allele-carrying cells. We found that miR-137 gain-of-function causes downregulation of the presynaptic target genes, Complexin-1 (Cplx1), Nsf, and Synaptotagmin-1 (Syt1), leading to impaired vesicle release. In vivo, miR-137 gain-of-function results in changes in synaptic vesicle pool distribution, impaired mossy fiber-LTP induction and deficits in hippocampus-dependent learning and memory. By sequestering endogenous miR-137, we were able to ameliorate the synaptic phenotypes. Moreover, reinstatement of Syt1 expression partially restored synaptic plasticity, demonstrating the importance of Syt1 as a miR-137 target. Our data provide new insight into the mechanism by which miR-137 dysregulation can impair synaptic plasticity in the hippocampus.

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“…Additionally, although many approaches have attempted to identify "molecular pathways" implicated in ASDs to unify disparate genes, these data have not converged to provide conclusive and well-replicated evidence. How these mutations lead to ASD phenotypes is poorly understood (for review see [91,92]). Hence, most cases still remain unknown, but potentially, including additional less penetrant rare variants or complex mechanisms, such as gene-gene interaction or gene-environment interaction.…”

Section: Molecular Pathways Asd: "Developmental Synaptopathies"mentioning

confidence: 99%

The Genetic and Epigenetic Basis Involved in the Pathophysiology of ASD: Therapeutic Implications

Carrascosa-Romero¹,

Cabo²

2017

Autism - Paradigms, Recent Research and Clinical Applications

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The prevalence of autism has increased in an exponential way in the past few years. Many monogenetic mutations as well as copy number variants and single nucleotide polymorphisms have been associated with autism spectrum disorders (ASD), a large proportion of which occur in genes associated with synaptogenesis and synaptic function. However, the increase in appearance of genetic alterations does not explain the etiology of an elevated number of ASD cases. Recent research is now focusing on the role of environmental/epigenetic factors, which by themselves and/or in combination with classical genetic factors, may be the root cause of a large number of ASDs. In this chapter we review the current literature regarding the epigenetic changes involved in ASD, including their possible mechanisms of action such as oxidative stress, altered fatty acid metabolism, mitochondrial dysfunction, DNA methylation and histone methylation (via the one-carbon metabolism cycle), histone variants, and ATP-dependent chromatin remodeling. We discuss possible new biochemical markers related to autism as well as new lines of research for therapeutic targets.

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Autism spectrum disorder causes, mechanisms, and treatments: focus on neuronal synapses

Cited by 170 publications

References 328 publications

Autophagy in synaptic development, function, and pathology

Autophagy in synaptic development, function, and pathology

The Schizophrenia Risk Gene Product Mir-137 Alters Presynaptic Plasticity

The Genetic and Epigenetic Basis Involved in the Pathophysiology of ASD: Therapeutic Implications

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